Fumarate hydratase variant prevalence and manifestations among individuals receiving germline testing.

BACKGROUND: Germline variants in fumarate hydratase (FH) are associated with autosomal dominant (AD) hereditary leiomyomatosis and renal cell cancer (HLRCC) and autosomal recessive (AR) fumarase deficiency (FMRD). The prevalence and cancer penetrance across different FH variants remain unclear. METHODS: A database containing 120,061 records from individuals undergoing cancer germline testing was obtained. FH variants were classified into 3 categories: AD HLRCC variants, AR FMRD variants, and variants of unknown significance (VUSs). Individuals with variants from these categories were compared with those with negative genetic testing. RESULTS: FH variants were detected in 1.3% of individuals (AD HLRCC, 0.3%; AR FMRD, 0.4%; VUS, 0.6%). The rate of AD HLRCC variants discovered among reportedly asymptomatic individuals without a clear indication for HLRCC testing was 1 in 2668 (0.04%). In comparison with those with negative genetic testing, the renal cell carcinoma (RCC) prevalence was elevated with AD HLRCC variants (17.0% vs 4.5%; P < .01) and VUSs (6.4% vs 4.5%; P = .02) but not with AR FMRD variants. CONCLUSIONS: The prevalence of HLRCC discovered incidentally on germline testing is similar to recent population carrier estimates, and this suggests that this is a relatively common cancer syndrome. Compared with those with negative genetic testing, those with VUSs had an elevated risk of RCC, whereas those with AR FMRD variants did not.

A Case of Left Ventricular Thrombus and Herpetic Esophagitis in an Immunocompetent Patient With COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been associated with thrombosis, both venous and arterial, but the mechanism behind this coagulation is not fully understood. Several cases involving coronavirus disease 2019 (COVID-19)-positive patients with left ventricular thrombus (LVT), particularly in those with low ejection fraction, have been reported. This report describes a case of a 57-year-old male patient who presented to the hospital with altered mental status and a positive SARS-CoV-2 polymerase chain reaction (PCR) test. CT of the chest revealed the presence of an LVT, and transthoracic echocardiography showed a reduced ejection fraction and confirmed the presence of the thrombus. The patient also reported epigastric chest pain and several bloody bowel movements. A colonoscopy revealed internal hemorrhoids. An esophagogastroduodenoscopy revealed the presence of multiple esophageal ulcers, and biopsy results confirmed herpes simplex virus (HSV) infection. The patient had no history of organ or bone marrow transplant, long-term immunosuppressive therapy, or HIV infection. He was eventually discharged on apixaban for his LVT and acyclovir for his HSV esophagitis.

The Impact of Granulocyte Colony-Stimulating Factor Administration in a Neutropenic Cancer Patient With COVID-19-Related Acute Respiratory Distress Syndrome.

Chemotherapy-induced neutropenia is a serious adverse effect found in cancer patients treated with chemotherapy. As these patients are at risk of infections, granulocyte colony-stimulating factors (G-CSF) are commonly used in these patients to increase neutrophil counts. This report describes a case of a 73-year-old female with metastatic breast cancer treated with letrozole and palbociclib who presented to the hospital with flu-like symptoms and a positive SARS-CoV-2 test. She was saturating well on room air without the need for supplemental oxygen initially, however, she was febrile and lab work revealed neutropenia. Subsequently, she was given two doses of Tbo-filgrastim. Her respiratory status deteriorated shortly afterward and she required supplemental oxygen. The chest X-ray obtained at that time revealed increased atelectasis or infiltration in the middle and lower lung fields, and computed tomography angiography of the chest revealed bilateral patchy airspace and ground glass opacities. The timeline from symptom onset along with her imaging findings suggested COVID-19-related acute respiratory distress syndrome (ARDS) as a possible explanation for her respiratory status decline. Interestingly, her neutrophil-to-lymphocyte ratio (NLR) had consistently increased, along with her respiratory status deterioration, after the completion of the two doses of G-CSF. The patient was treated with dexamethasone. Her respiratory status eventually improved prior to discharge.

Fumarate Hydratase Variants and Their Association With Paraganglioma/Pheochromocytoma.

OBJECTIVE: To clarify the link between germline variants in fumarate hydratase (FH), hereditary leiomyomatosis and renal cell cancer (HLRCC), and paraganglioma (PGL) and pheochromocytoma (PCC) we utilize a well-annotated hereditary cancer testing database. METHODS: Records of 120,061 patients receiving germline testing were obtained. FH variants were classified into 4 categories: autosomal dominant (AD) HLRCC variants, autosomal recessive (AR) fumarase deficiency (FMRD), variants, previously reported as PGL/PCC FH variants, and variants of unknown significance (VUS) not previously associated with PGL/PCC (NPP-VUS). Rates of PGL/PCC were compared with those with negative genetic testing. RESULTS: About 1.3% of individuals carried FH variants which were more common among individuals with PGL/PCC compared to those without (3.1% vs 1.3%, P < .0001). PGL/PCC rates were higher among individuals with PGL/PCC FH variants compared to those with negative genetic testing (22.2% vs 0.9%, P < .0001). Neither AD HLRCC variants (0.3% vs 0.9%, P = .35) nor AR FMRD variants (1.4% vs 0.9%, P = .19) carried an increased prevalence of PGL/PCC. An increased prevalence of PGL/PCC was detected in those with NPP-VUS (2.0% vs 0.9%, P = .0023). CONCLUSIONS: Certain FH variants confer an increased risk of PGL/PCC, but not necessarily HLRCC. While universal screening for PGL/PCC among all individuals with FH variants does not appear warranted, it should be considered in select high-risk PGL/PCC FH variants.